You are on page 1of 15

Executive Summary of MRC’s Legal Analysis on AMARIN PHARMA,

INC., et al., Plaintiff(s), v. HIKMA PHARMACEUTICALS USA, INC., et al.,


Defendant(s); Case No.: 2:16-cv-02525-MMD-NJK

Introduction
Following is an executive summary of a legal analysis on Case No.: 2:16-cv-02525-MMD-NJK by
Medical Research Collaborative, LLC (“MRC,” “we,” “us,” etc.). We find that not only are the 10
asserted claims at trial both explicitly and inherently obvious, but further, that Amarin cannot
demonstrate “by a preponderance of evidence” that Defendants’ ANDA labels “show intent to
encourage” clinicians to infringe upon any of the asserted claims, and that in order for Judge Du
to issue this ruling, it would require her to defy clear precedent in multiple Federal Circuit
rulings (and/or inconceivably misunderstand their most apparent interpretation), as well as
usurp well-established rules contained in the Code of Federal Regulations (“C.F.R.”)—in short,
go rogue. Nothing revealed in the trial proceedings or in Amarin’s pre- or post-trial documents
has altered our point of view. Thus, our odds of Amarin winning the litigation remain paltry (<
15%).

Executive Summary

I. The crux of Amarin’s claims recite a method of administering highly purified


(~96%) ethyl-EPA to patients with TG levels >/= 500 mg/dL to (a) reduce serum TG
levels (b) without effecting an increase in LDL-C, and (c) without increasing and/or
to effect a decrease in apoB. However, these claims are invalid as obvious.

The question of obviousness turns on whether or not a person of ordinary skill in the art, aka
“POSA” (a hypothetical “person” denoting the cumulative knowledge of all persons skilled in
the art at the time of the invention, well versed in all writings on the topic in all
languages/dialects, including all related patents—i.e., all “prior art”—and the totality of their
cross-referenced inferences—i.e., what combining two or more prior art references would

1
reveal, even if no single reference mentions this directly), would have been motivated to try the
claimed invention, and would have had at least a “reasonable expectation” it would succeed.1
‘Obviousness requires assessing (1) the “level of ordinary skill in the pertinent art,” (2)
the “scope and content of the prior art.” (3) the “differences between the prior art and
the claims at issue,” and (4) “secondary considerations” of non-obviousness such as
“commercial success, long-felt but unsolved needs, failure of others, etc.” KSR Int'l Co. v.
Teleflex Inc., 550 U.S. 398, 406, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) (quoting Graham
v. John Deere Co., 383 U.S. 1, 17–18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966)).
A party seeking to invalidate a patent as obvious must demonstrate “ ‘by clear and
convincing evidence that a skilled artisan would have been motivated to combine the
teachings of the prior art references to achieve the claimed invention, and that the
skilled artisan would have had a reasonable expectation of success from doing so.’ ”
Procter & Gamble Co. v. Teva Pharms. USA, Inc., 566 F.3d 989, 994 (Fed.Cir.2009)
(quoting Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1361 (Fed.Cir.2007)).’
The prior art (pre ca. 2008) is replete with examples of testing the exact formulation as
Vascepa, containing the same high-purity ethyl-EPA described in the patent claims, and often at
the same 4 g/d dose, showing a marked lowering-effect on TG levels while also showing no
significant increase in LDL-C or apoB, with some studies also showing a significant decrease in
apoB (Grimsgaard, Kurabayashi, etc.). In fact, of the scores of studies testing high-purity EPA in
subjects with a wide range of elevated to very-high TG levels (including some subjects with TG
levels > 500 mg/dL), there are astoundingly few that show any increase in LDL-C or apoB.
Contrastingly, there are an abundance of studies that tested mixed omega-3 formulations
containing significant amounts of DHA, as well as studies testing > 90% pure DHA formulations,
which show LDL-C-raising (and at times apoB-raising) effects in its subjects. And in multiple
published pre-ca. 2008 studies there is commentary expressly stating that such LDL-C elevations
appear attributable to DHA but not EPA.2, 3 In fact, before Amarin ever had results from the
MARINE trial showing a lack of LDL-C elevation in severe hypertriglyceridemia (SHTG) subjects
dosed with 4 g/d Vascepa, they filed the patents in contention. Thus, they were relying only on
prior art as “motivation to try” themselves. They even presented the following charts to
prospective investors (pictured below—including some commentary from Defendants):4

1
https://casetext.com/case/bristol-myers-squibb-co-v-teva-pharm-usa-inc-1
2
https://academic.oup.com/ajcn/article/79/4/558/4690135 “The striking finding in the present study was the
LDL cholesterol–raising effect of a relatively modest intake of DHA. The increase was 7% greater than that
seen with placebo. This observation is not likely to be due to chance, because the study had sufficient power
to detect the observed change. Furthermore, we have confirmed this observation in a subsequent study (TAB
Sanders, GJ Miller, unpublished observations, 2002). Studies using purified EPA or EPA-rich oil have generally
not reported increases in LDL cholesterol.”
3
https://academic.oup.com/ajcn/article/71/5/1085/4729166 “Serum LDL cholesterol increased significantly
with DHA (by 8%; P = 0.019), but not with EPA (by 3.5%; NS).”
4
ECF No. 373, at 186

2
3
This is clear evidence of obviousness. In other words, “that a skilled artisan would have been
motivated to combine the teachings of the prior art references to achieve the claimed
invention, and that the skilled artisan would have had a reasonable expectation of success from
doing so.”
Not to mention the exact same formulation as Vascepa, known as “Epadel,” was already
approved in Japan ca. 1990 for “arteriosclerosis obliterans” and ca. 1994 for “hyperlipidemia,”
an umbrella heading that includes “severe hypertriglyceridemia”—of course, the exact same
indication that is under contention here. The Epadel label since ca. 1994 has stated, "1) EPA-E
has proved to decrease the serum lipids (total cholesterol, triglycerides, etc.) in patients with
various types of thrombotic and arteriosclerotic disease. 2) EPA-E has proved to exert a
hypolipidemic effect..." Not to mention the success of the JELIS study gave even further
“motivation to try,” as that study showed 1.8 g/d of high-purity ethyl-EPA significantly reduced
the risk of MACE by 19%. Thus, by getting approval for severe hypertriglyceridemia, an
inventor/drug-sponsor could also potentially enjoy many off-label prescriptions for patients at
risk for ASCVD. In essence, Amarin simply and quite clearly copied Mochida, and did nothing
truly innovative on their own.
Further, the initial prosecution of Amarin’s patents included numerous rejections, in part
because the examiner determined that the prior art “Hayashi” included subjects with baseline
TG levels over 500 mg/dL (“300 ± 233 mg/dL”), thus including an “overlap” of subjects that had
a key characteristic described in the claims. Amarin then had a Dr. Lavin submit a declaration
that stated, “not even one patient in the study would be expected to have a TG level of 450
mg/dL or higher” in Hayashi.5 This, combined with other errant conclusions (e.g., that no prior
art showed apoB reduction from high-purity EPA administration, which is false), convinced the
examiner to allow the patents. Later, Dr. Lavin testified that he was incorrect in his assertions
on Hayashi, and would “rewrite” his declaration if he could.6
The USPTO examiner also did not locate other prior art that clearly included subjects with TG
levels >/= 500 mg/dL. For example, in addition to Hayashi (treating patients with a triglyceride
level of 300 ± 233 mg/dL), there was Matsuzawa (treating patients with a mean triglyceride
level of 308 ± 70 mg/dL, with 3 patients having a triglyceride level between 400 and 1000
mg/dL, and one with a triglyceride level over 1000 mg/dL); Saito (subject with serum
triglycerides greater than or equal to 500 mg/dL); and Nakamura (subject with serum
triglycerides of approximately 560 mg/dL).7

5
ECF No. 333, at 9.
6
ECF No. 373 at 58: ‘Although Dr. Lavin initially told the PTO that not even one patient in Hayashi would have had
triglyceride levels > 500 mg/dL, Dr. Lavin later testified that he would “rewrite” his declaration on this point,
explaining that in Hayashi “you know that there must be at least one subject” with triglyceride levels > 500 mg/dL,
and that it is “likely that you have one or two observations above 533.” Lavin Dep. Tr. at 102:24-103:21.’
7
ECF No. 333 at 74

4
The examiner also did not find Kurabayashi or Grimsgaard, which both showed significant
reduction in apoB from high-purity EPA dosing—and Grimsgaard showed this in contrast with a
high-purity DHA arm, and was a robustly sized study (equal in number of subjects per arm with
Amarin’s MARINE trial).
All told, the initial prosecution of the patents at issue was subpar (as effectively argued by
Defendants), and the court will recognize this.
Furthermore, secondary considerations (such as “unexpected results”) are problematic and
weaker as evidence of nonobviousness. There is also the matter of degree vs. kind, with a
difference in degree between the prior art and the claimed invention often being insufficient as
evidence of nonobviousness versus a difference in kind. In this case, no significant change in
median LDL-C and a significant decrease in median apoB, as noted in the Clinical Studies
sections of the ANDA (generic drug) labels, is a matter of “degree,” not “kind,” and are
secondary considerations (purportedly “unexpected results”). Of course, a number of subjects
saw an increase in both markers in MARINE, as well as increases, decreases, or no change in
LDL-C/apoB in many other omega-3 and EPA-only studies conducted in subjects with a variety
of baseline TG levels. In short—it’s not a wholly new phenomenon, and as such cannot be a
new “kind” of effect.
An apt example from case law is Bristol-Myers Squibb Co. v. Teva Pharmaceuticals USA, Inc.,
752 F.3d 967 (Fed. Cir. 2014), wherein the Federal Circuit agreed with the district court that
found the claims at issue invalid as obvious—despite valid unexpected results—noting:
“Contrary to BMS's argument, unexpected results do not per se defeat, or prevent, the
finding that a modification to a lead compound will yield expected, beneficial
properties. Rather, as secondary considerations of nonobviousness, they come into play
in determining “the ultimate question of patentability.” Dillon, 919 F.2d at 692–93;
Procter & Gamble, 566 F.3d at 997–98 (citing to Dillon and finding evidence of superior
properties such as potency and safety that were “unexpected and could not have been
predicted” could outweigh evidence of obviousness).
We have held an invention to be obvious despite findings of unexpected results. See,
e.g., Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286, 1293 (Fed.Cir.2013); Alcon Research,
Ltd. v. Apotex, Inc., 687 F.3d 1362, 1365, 1369–70 (Fed.Cir.2012); Pfizer, 480 F.3d at
1372.
Secondary considerations of nonobviousness “must always when present be
considered,” and can serve as an important check against hindsight bias. See
Cyclobenzaprine, 676 F.3d at 1075–76, 1079 (quoting Stratoflex, Inc. v. Aeroquip Corp.,
713 F.2d 1530, 1538–39 (Fed.Cir.1983)). While secondary considerations must be taken
into account, they do not necessarily control the obviousness determination. Pfizer, 480
F.3d at 1372; see also KSR, 550 U.S. at 426, 127 S.Ct. 1727. Here, the district court found
evidence of some secondary considerations of nonobviousness, including commercial
5
success, long-felt need, and unexpected results. On appeal, BMS focuses primarily on
unexpected results.
…[W]hile the district court found that entecavir's degree of effectiveness was
unexpected, it also noted that entecavir's ‘effectiveness against hepatitis B without
known toxicity issues’ was ‘not unexpected’ in light of the structurally similar 2'–CDG.
J.A. 150. As for the high genetic barrier to resistance, the district court properly credited
this attribute as an unexpected property. All taken together, the district court found
that the proffered evidence of unexpected properties provided ‘some support to BMS's
argument as to nonobviousness,’ but did not find it sufficient. J.A. 151–53…
We agree with the factual findings on secondary considerations and find no clear error.”
Thus, although there was an unexpected degree of a desirable effect, and although one effect
was entirely unexpected in kind, the prior art “taken as a whole” was found to teach the
claimed invention in BMS, and thus the claims at issue were deemed invalid as obvious. In the
above case, such secondary considerations, although in large part valid, were insufficient to
overturn obviousness.
We find the same to be true of Amarin’s patents, which are primarily about the TG-lowering
effect of an Epadel knock-off (i.e., Vascepa), with the added, unexpected (according to Amarin)
side benefits of a lack of increase in median LDL-C, and a small but significant decrease in
median apoB—which are not even differences in kind, but degree only (and importantly, are
noted as “median” values in the label). Further, the ANDA labels under contention are only
indicated to treat SHTG, with no mention of LDL-C or apoB in the Indications and Usage section.
In sum, Amarin’s patents were filed before the MARINE trial data were had, and the claims
were not based on anything other than extrapolations of prior art references. Amarin
themselves admitted as much in the above advert materials, clearly arguing that prior studies
revealed DHA, but not EPA, caused an increase in LDL-C. And this was also before having
unblinded MARINE trial data. Further, the examiner displayed a lack of due diligence by failing
to find key prior art references, and was also persuaded by what was later found to be an
erroneous expert declaration. And lastly, secondary considerations of nonobviousness (in this
instance, a lack of increase in LDL-C and a decrease in apoB, being in Amarin’s view
“unexpected results”—and the purported “long felt need” of reducing TG levels without
increasing LDL-C) are inherently weak, and must be exceptional to support an overall finding of
nonobviousness—but are usually considered unsupportive as evidence if only a difference in
degree rather than kind. Yet, even if considered a difference in kind (which we think unlikely to
be the court’s view), the prior art clearly taught such a profile from EPA, both implicitly (in
subjects with high TG levels, but less than 500 mg/dL), and explicitly (in subjects with TG levels
> 500 mg/dL). Thus, the claims are at least inherently, but likely also explicitly, obvious.

6
II. Even if Amarin’s patents are upheld as nonobvious based on secondary
considerations, Defendants’ ANDA labels do not show specific intent to induce
clinicians to prescribe based on the purported “Other Health Benefits,” namely a
lack of increase in LDL-C and a decrease in apoB, because such are unapproved
uses, and the ANDA labels cannot be found to induce clinicians to infringe by
prescribing for unapproved uses, which are not validated by “substantial evidence
of effectiveness.”

“The patentee bears the burden of proving infringement by a preponderance of the evidence.
If the patentee fails to meet that burden, the patentee loses regardless of whether the accused
comes forward with any evidence to the contrary.” Creative Compounds, LLC v. Starmark Labs.,
651 F.3d 1303, 1314 (Fed. Cir. 2011).
In Hatch-Waxman cases involving method-of-treatment claims, “the question of induced
infringement turns on whether [defendants] have the specific intent, based on the contents of
their proposed labels, to encourage physicians to use their proposed ANDA products to treat
[patients in an infringing manner]. In other words, we ask whether the label encourages,
recommends, or promotes infringement.… The pertinent question is whether the proposed
label instructs users to perform the patented method.” Grunenthal GMBH v. Alkem Labs. Ltd.,
919 F.3d 1333, 1339 (Fed. Cir. 2019).
To prove induced infringement, “[m]erely describing the infringing use, or knowing of the
possibility of infringement, will not suffice; specific intent and action to induce infringement
must be shown.” HZNP Medicines LLC v. Actavis Labs. 940 F.3d 680, 701 (Fed. Cir. 2019)
(“Horizon”); see also Takeda Pharm. U.S.A., Inc. v. W.-Ward Pharm. Corp., 785 F.3d 625, 631
(Fed. Cir. 2015) (“The question is not just whether instructions describe the infringing mode,
but whether the instructions teach an infringing use of the device such that we are willing to
infer from those instructions an affirmative intent to infringe the patent. Merely describing an
infringing mode is not the same as recommending, encouraging, or promoting an infringing use,
or suggesting that an infringing use ‘should’ be performed. The label must encourage,
recommend, or promote infringement. The mere existence of direct infringement by
physicians, while necessary to find liability for induced infringement, is not sufficient for
inducement.” (quotations and alterations omitted)); ECF No. 294 at 40 (Amarin’s statement of
issues of law quoting Takeda standard).
Thus, we have our standard by which Amarin must prove ANDA labels show “specific intent to
encourage, recommend, or promote infringement” of the so called “Other Health Benefits”
claims—namely, “without increasing LDL-C” and “to effect a decrease in apoB.” Has, or even
can Amarin meet its burden of proving that ANDA labels show specific intent to encourage
clinicians to prescribe Vascepa due to a lack of effect on LDL-C and/or a minor decrease in
apoB? In our view, that bar is impossibly high to scale.

7
All of Amarin’s arguments succinctly fail in the face of Bayer Schering Pharma AG v. Lupin, Ltd.
676 F.3d 1316 (Fed. Cir. 2012).8
Case law has repeatedly demonstrated that not just any mention of efficacy or safety in a
reference listed drug (RLD) label, and thereby identical ANDA label, may induce infringement by
marketing a generic version of the drug, but only what is stated, referenced in, or required by
the “Indications and Usage” and/or “Dosage and Administration” sections. This topic was
covered in detail in Bayer.
The RLD in question was “Yasmin” (drospirenone), an oral contraceptive marketed by Bayer. In
the Indications and Usage section of the Yasmin drug label it only states the use of Yasmin for
oral contraception. But elsewhere in the label (in the Clinical Pharmacology section) are studies
that show an effect of Yasmin that is both anti-androgenic (anti-acne) and anti-aldosterone
(diuretic), and affirming statements as to these effects. Bayer’s US Pat. No. 5,569,652 claims all
three effects of Yasmin. One of the three (oral contraceptive) was off-patent.
The district court ruled in favor of ANDA filers, stipulating that the use must be mentioned in or
proceed from the Indications and Usage section in order to be infringed upon. The case was
appealed, and the Federal Circuit agreed with the district court.
The Bayer court noted the following [brackets and emphasis ours]:
“The portion of the regulation that is addressed to the Indication & Usage section of the
label requires the indications set forth in that section to be supported by ‘substantial
evidence of effectiveness based on adequate and well-controlled studies.’
(§201.57(c)(2)(iv). The regulation adds that indications or uses ‘must not be implied or
suggested in other sections of the labeling if not included in this section.’ The reference
in the Clinical Pharmacology [or Clinical Studies] section of the label... is certainly not a
direct indication of an appropriate use for Yasmin [or Vascepa], and even if it could be
considered an ‘implied or suggested’ indication of an approved use, the regulation
expressly states that such implied or suggested uses do not constitute approved uses.
In addition, the FDA regulation requires the label to provide a summary of the essential
scientific information needed for the safe and effective use of the drug. See 21 C.F.R.
201.56(a)(1). The [Vascepa] label does not provide physicians with such a summary with
respect to the drug’s [lack of effect on LDL-C or effect on apoB]... which is further
indication that the FDA did not approve the use of [Vascepa] to exploit those effects in
treating patients.”
And:
“Acknowledgement of the safety and efficacy of that specific method of use [to very
modestly reduce apoB from baseline by 3.8%, or have no statistically significant effect

8
https://casetext.com/case/bayer-schering-pharma-ag-v-lupin-ltd-2

8
on LDL-C] would be evidenced by including it in the Indications & Usage section of the
label.”
Thus, as mentioned, there must exist a nexus to the Indications & Usage section for an effect
(or presumed lack of effects, which are endless) stated elsewhere in the label to be considered
in any way an approved use, validated by “substantial evidence of effectiveness.” This includes
important safety signals (e.g., no increase in LDL-C) as well as efficacy (e.g., decrease in apoB).
The observation of a meager, median 3.8% reduction in apoB from baseline—or even the 8.5%
placebo-corrected median reduction, which was similar in ANCHOR (-8.8% placebo-corrected9),
and unconvincing to FDA, who issued a CRL to Amarin that sought an expanded label based on
this and other data—as well as the lack of change in median LDL-C (which is problematic, as it is
not a “use,” per se, nor are any non-effects validated effects, only statistically significant effects
are—and being that it is a median value, almost half saw an increase in LDL-C), cannot be said
to be “substantia[ted]” by “evidence of effectiveness,” as they are not approved uses that
proceed or are referenced in any manner from the all-important Indications & Usage section.
And of course, the Code of Federal Regulation (C.F.R.) also stipulates the “Clinical Studies”
section specifically, “must not imply or suggest indications or uses... not stated in the Indications
& Usage or Dosage & Administration section.” 21 CFR § 201.57(c)(15)(i).
Amarin spends a good deal of time in their pretrial findings pointing out areas in FDA guidance
documents that in their view help their argument of equal weighting given by a physician to
multiple sections of a drug label in determining how to prescribe a drug for their patient. Of
course, consideration of each section of a label is important, but these mentions in guidance
are misconstrued by Amarin to mean: ‘all sections have equal weighting, and thus, if just one
section mentions a use, the entire label encourages the use.’ For instance, although the label
should be considered “in its entirety,” this does not mean that uses described outside of the
Indications & Usage section are approved uses, validated by “substantial evidence of
effectiveness,” unless that section refers to and/or requires them. Amarin wishes “in its
entirety” to mean that if any section refers to the claimed use, then the label “in its entirety”
teaches the claimed use. That is false. In fact, the burden is far higher—that the entire label
must drive a prescriber towards the claimed use, not just one jot or one allusion in a given
section—especially not if the purported use exists only in a section outside of the three most
important sections of the label (i.e., Ind & Use, Dose & Admin, and Summary), without any clear
nexus directing a clinician to it.
Furthermore, guidance documents represent “current thinking” of the FDA and are not “legally
binding on the agency.” The FDA has oftentimes acted contrary to guidance documents, and/or
changed future versions of them to such a degree as to make older guidance docs no longer

9
https://www.sciencedirect.com/science/article/pii/S1933287414004085

9
valid. Amarin even points to certain “draft” guidance docs, which are not “final” versions,
meaning they are works in progress, and the content not yet substantiated.
These are contrasted with well-established rules contained in the Code of Federal Regulations,
which has a higher authority than FDA guidance documents (or any expert testimony), and
upon which the Federal Circuit in Bayer relied.
Stated another way: no use of a drug that a physician of their own accord confers from a
section outside of the Indications & Usage, Dosage & Administration, or Summary (i.e.,
“Highlights”) sections, without a clear nexus from within these sections driving a clinician to
that use, is validated as an approved use based upon “substantial evidence of effectiveness.”
Thus, and de facto, there is no “substantial evidence” to establish the purported use’s
“effectiveness,” and the label “in its entirety” cannot be construed as “encouraging,
recommending, promoting, or suggesting that clinicians use the generic drug product in [that]
manner.” This is unassailable fact.
An apt example comes from the IMPROVE-IT trial, testing ezetimibe.10 That trial showed a
statistically significant finding of a reduction in MACE. However, the FDA, after thorough
review, did not approve the drug for that indication, citing the ~6% risk reduction as not
clinically meaningful, even though statistically significant.11
If the label for ezetimibe were to contain information on MACE reduction from the IMPROVE-IT
trial in the Clinical Studies section, while only containing “to effect a reduction in LDL-C in those
with an elevation” in the Indications & Usage section, an identical generic label could not be
found to induce infringement of a MACE reduction claim based on the information contained in
the Clinical Studies section that is not contained in or referred to by the Indication & Usage
section, as the ~6% reduction in MACE is not a validated use based on “substantial evidence of
effectiveness.” A generic label cannot be found to induce infringement of non-validated,
purported uses that are lacking in “substantial evidence of effectiveness.” If a clinician
prescribes thus, they do so of their own accord in an off-label manner—even if based on
information in the label itself. The Bayer court confirmed this view, stating, “Therefore,
notwithstanding Dr. Shulman's understanding to the contrary, any prescription of Yasmin to
produce either an anti-mineralocorticoid or anti-androgenic effect has not been approved by
the FDA and is therefore ‘off label,’ [even though such effects are found in the Clinical
Pharmacology section of the drug label].”
Amarin also repeatedly errs in its many comparisons with other TG-lowering therapies. In order
to show that Vascepa is significantly different from Lovaza or other formulations that contain
prominent amounts of DHA with regard to an effect on LDL-C/apoB, a head-to-head trial testing
these outcomes between the two formulations would need to be conducted. We cannot
accurately contrast results from one trial to another trial and draw valid conclusions that have

10
https://www.medscape.com/viewarticle/845866
11
https://www.medscape.com/viewarticle/858944

10
scientific merit.12 Such would be an invalid comparative method that suffers from issues of
multiplicity due to clinical heterogeneity. Although meta-analyses perform such comparisons,
they involve complicated “adjustments” to help account for imbalances in study populations
between trials. And even then, the results are prone to bias and must be interpreted with
caution. However, a drug would never be approved by FDA based on mere meta-analyses. And
for good reason.13
Amarin commits this error when they compare other drug labels with the Vascepa label,
showing differences in side-effects based on different trials that inform each individual label.
They also commit the error anytime they state FDA recognizes the “lack of significant change in
LDL-C” and small “3.8% decrease in apoB from baseline”14 as validated treatment effects,
especially as may be compared with other therapies based on data from other clinical trials.
In order to prove Vascepa does not increase LDL-C but Lovaza (or Tricor) does, a head-to-head
trial that can highlight significant differences in treatment effects between the therapies in
randomized subjects of equivalent baseline characteristics would need to be conducted.
Otherwise, the lack of impact on LDL-C is not an effect at all, especially as their assumption is
that the effect of an increase in LDL-C, as seen in the Lovaza study in severe
hypertriglyceridemia subjects (see label15—42 treatment vs 42 placebo subjects), would not
have occurred if Vascepa was given in the same subjects instead. That is invalid. Perhaps this
hypothetical Vascepa group would have seen a significant increase in LDL-C in the majority of its
subjects (rather than an insignificant increase in just under half, as in MARINE), as they were a
different group of persons with different background medications and different baseline
lipid/lipoprotein levels—and the trial included fewer subjects, which increases variability, and
the chance of observing an “off-treatment” effect. And importantly, the baseline median TG
levels of subjects in the Lovaza study were higher than those in MARINE (816 mg/dL in Lovaza
study vs 680 mg/dL in MARINE16).
In sum, the Vascepa label, including the MARINE trial results themselves, do not in isolation
validly show that EPA-containing formulations decrease apoB and cause no change in LDL-C,

12
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116848/
13
https://www.mdedge.com/ccjm/article/94919/practice-management/meta-analysis-its-strengths-and-
limitations
14
In a letter from FDA to Amarin on promoting ANCHOR results, FDA stated “…To the extent you choose to provide
a summary that is different from Exhibit B, FDA would not consider it false or misleading or its distribution
evidence of intended use if the summary remains factual, does not omit material information, and does not
otherwise introduce bias. In particular, the communication could be misleading if it implied or suggested that the
ANCHOR study supports the conclusion that lowering triglyceride levels lowers the risk of CVD in patients already
treated with statins or that available evidence establishes that there is a clinical benefit in lowering TG levels for
patients with high TG levels. We also believe that to avoid being misleading, any summary would show not only
the differences between Vascepa and the mineral oil placebo, but also changes from baseline to endpoint in each
of the treatment groups…” due to, inter alia, the potential the mineral oil placebo was not inert.
15
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021654s043lbl.pdf
16
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202057Orig1s000MedR.pdf

11
neither on its own, nor especially if erroneously compared with DHA-containing formulations
(i.e., other labels). Those purported “effects” are in fact not substantiated by the Vascepa label.
Another arm of the trial would have been needed to show this, where subjects of equal
baseline characteristics could have been given 4 g/d Lovaza vs 4 g/d Vascepa vs placebo (similar
in design with Grimsgaard et al. 1997). But that of course wasn’t done.
The whole premise being made by Plaintiffs is faulty; if clinicians make the ill-founded
assumption that Vascepa can cause a clinically meaningful reduction in apoB and not effect LDL-
C in subjects with baseline TG-levels of exactly 500 mg/dL (and the claims do not require any
more than this) based on information outside of, and not referred to by any of the three most
important sections of the drug label—and further make the assumption that Vascepa is
superior to Lovaza in these regards—they do so in as scientifically invalid manner. ANDA labels
simply cannot be found to induce infringement of what is scientifically invalid.
Bayer makes the unassailable case that nothing in an ANDA label can cause infringement if it is
not also in the “Indications and Usage” or “Dosage and Administration” sections, or distinctly
referred to/required by one of these sections—for the very reasons expressed above. And of
course, mentions of LDL-C/apoB are not included in these sections of DRL/Hikma’s ANDA labels,
nor can be inferred from these sections in any manner.
Although it would have been inappropriate to overlook expert testimony in Summary
Judgement phase by ruling in Defendants’ favor, and although the court must look to expert
testimony to make determinations on labeling and inducement—in our view, the court must
ultimately find Defendants’ ANDA labels do not show “specific intent… to encourage”
physicians to infringe on the “Other Health Benefits” claims, as they are listed in the “Clinical
Studies” section only, and not referred to in any manner in other (highly important) sections of
the ANDA labels. For Judge Du to rule otherwise would be in direct contradiction to such black-
and-white remarks from the Federal Circuit in Bayer, such as:
‘The FDA labeling regulation, 21 C.F.R. § 201.57, makes clear that the FDA has not
approved the use of Yasmin to produce the pharmacological effects that are listed in
the Clinical Pharmacology section of the label. The portion of the regulation that is
addressed to the Indications and Usage section of the label requires the indications set
forth in that section to be supported by “substantial evidence of effectiveness based
on adequate and well-controlled studies.” Id. § 201.57(c)(2)(iv). The regulation adds
that indications or uses “must not be implied or suggested in other sections of the
labeling if not included in this section.” Id. The reference in the Clinical Pharmacology
section of the label to the antimineralocorticoid and anti-androgenic activity of
drospirenone is certainly not a direct indication of an appropriate use for Yasmin, and
even if it could be considered an “implied or suggested” indication of an appropriate
use, the regulation expressly states that such implied or suggested uses do not
constitute approved uses.

12

Bayer points out that the sections of the regulation directed to the Indications and
Usage portion of the label address only “the portion of the labeling that can detail the
diseases or conditions the FDA has approved the drug to treat,” and that other effects
“that do not treat a disease or condition will not be in the Indications section and will
still be FDA approved.” However, whether other effects may be described outside the
Indications and Usage section of the FDA-approved label does not address the issue in
this case… [T]he fact that certain of the effects of a drug are described in the Clinical
Pharmacology section of the label does not mean that the FDA has approved the use
of the drug to produce those effects; it only ensures that physicians are aware of the
full range of the drug's pharmacological effects (especially those that might be
considered adverse effects) when prescribing the drug for a purpose set forth in the
Indications and Usage section and under the conditions described in other parts of the
label.’

To practice the method claimed in the ′652 patent, a physician must determine that all
three effects are needed by a specific premenopausal or menopausal patient. FDA
approval of that method of use would require a showing that Yasmin was safe and
effective for simultaneously obtaining those three effects in patients needing those
effects. Acknowledgement of the safety and efficacy of that specific method of use
would be evidenced by including it in the Indications and Usage section of the label…”
Once again, although unable to rule in Defendants’ favor during SJ phase, how could Judge Du,
with the above very clear assertions from the Federal Circuit in mind, possibly rule in Amarin’s
favor that ANDA labels would infringe on the “Other Health Benefits” claims, when such uses
are not listed or even implied in the “Indications and Usage” or “Dosage and Administration”
(or Summary) sections—and when the only apparently contradictory ruling in Sanofi was not a
contradiction at all, because the Ind & Use section of that label specifically directed a prescriber
to the Clinical Studies section to determine which patients were best suited for the drug:
“Multaq® is indicated to reduce the risk of hospitalization for atrial fibrillation in
patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF)
[see Clinical Studies (14)].”
The Sanofi court found that “the label thus directs medical providers [from the Indication &
Usage section] to information [in the Clinical Studies section] identifying the desired benefit for
only patients with the patent-claimed risk factors.”
Amarin’s case is most similar to Bayer, where the purported uses are only located in one
section, and not referenced in any manner by the Ind & Use section, making them decidedly not
validated by “substantial evidence of effectiveness.”

13
This clear decision in Bayer also occurred in the face of contrary, reputable expert testimony.
The Fed. Cir. noted:
“The record contains, among other evidence, the expert declaration of Dr. Allen, FDA
past Director of the Division of Reproductive and Urologic Drug Products, that these
effects were demonstrated when Yasmin® was presented for FDA approval. Dr. Allen
states:
‘Each of the three effects identified in Claim 11 of the '652 Patent are listed in the
professional labeling for Yasmin®.... The inclusion of statements describing these
three effects in the FDA-approved labeling means that the FDA approved (a) the
therapeutic effect (contraceptive) and (b) the two additional pharmacological
effects (anti-androgenic and anti-mineralocorticoid) of Yasmin®. When the FDA
approved the Yasmin® NDA, it “concluded that adequate information has been
presented to demonstrate that the drug product is safe and effective for use as
recommended in the agreed upon enclosed labeling test.” FDA Approval Letter
(May 11, 2001).’
Dr. Shulman, a leading obstetrician-gynecologist with extensive experience in oral
contraceptive research and clinical use, stated in his declaration that prescriptions of
Yasmin® as an oral contraceptive with intent to produce the two further
pharmacological effects are “on-label,” and that he prescribes Yasmin® for these
additional pharmacological effects. Dr. Shulman stated:
‘The physician labeling for Yasmin® contains the data supporting the use of Yasmin®
in the treatment method of claim 11 of the '652 patent.... Because drospirenone
has anti-mineralocorticoid activity as disclosed in the Clinical Pharmacology section,
the prescription of Yasmin® as an oral contraceptive with the intent to produce an
anti-mineralocorticoid pharmacological effect is clearly stated and on-label....
Because drospirenone has anti-androgenic activity, the prescription of Yasmin® as
an oral contraceptive with the intent to produce an anti-androgenic
pharmacological effect is clearly stated and on label.... I have prescribed Yasmin®
for premenopausal women in accordance with claim 11 of the '652 patent, continue
to do so, and consider such prescriptions to be on-label…’ ”
The Bayer court was correctly not convinced by these admissions, and neither should Judge Du
be convinced by similar admissions from Amarin’s experts regarding the Vascepa label.

14
What is Infringed, is Obvious
The only remaining claim being asserted at trial that does not mention/is limited by the LDL-C
and apoB effects/lack thereof, and would in fact be infringed upon (albeit indirectly--“inducing”
a clinician) by the ANDA labels, is claim 1 of the ‘929 patent. This claim is recited below:
1. A method of reducing triglycerides in a subject having fasting triglycerides of at least
500 mg/dl comprising, orally administering to the subject daily for at least about 12
weeks a pharmaceutical composition comprising about 4 g ethyl eicosapentaenoate and
not more than about 4% docosahexaenoic acid or its esters, by weight of all fatty acids.
However, in ECF No. 262, exhibit 18, the patent examiner’s prosecution of Amarin’s patents
included the following statements:
“The prior art does not teach the administration of ethyl-EPA to patients having TG
levels between 500 and 1500 mg/dl (very high), as such there is no anticipation.
However, the prior art teaches that: 96% pure ethyl-EPA has been administered to
patients with TG levels between 150- 499 mg/dl (borderline high/high) in order to lower
TG levels in amounts that range from 1.8 g per day up to 4.0 per day and for periods of
time ranging from a few weeks up to two years (see non-final rejection dated
03/02/2012, pages 4 through page 7, first paragraph). In every case a substantial
reduction of TG levels was observed. The prior art also teaches that the administration
of a mixture of ethyl-EPA and DHA (also known as Lovaza or Omacor) to patients with
TG levels above 500 mg/dl (very high). The results show a dramatic reduction in TG
levels (about 50%). Based on these references it was concluded that it will be obvious to
treat patients having TG above 500 mg/dl with 96% pure ethyl-EPA (see pages 7 and 8 of
the non-final rejection dated 03/02/2012).”
That settles the matter. And Amarin is not arguing otherwise at trial.

Conclusion

We find Defendants’ case to be overwhelmingly strong, even without any reliance upon the
much-discussed “12-weeks” limitation present in all claims, which arguments we find to be
weaker than the above against inducement. When taken as a whole, it is clear the prior art both
implicitly and explicitly teaches each element of the claimed invention, both in terms of
motivation to try, as well as “reasonable” expectation of success, as the prior art clearly
differentiates between the effects of DHA and EPA, and even explicitly implicates DHA as the
likely cause behind an increase in LDL-C, while concurrently exonerating EPA in this regard.
Amarin themselves highlighted such prior art to prospective investors before ever having
known results from the MARINE trial. Furthermore, without any allusion to the “Other Health
Benefits” claims in the Indications & Usage section, and with these being contained only in the
Clinical Studies section, even if the claims are found nonobvious based merely on secondary
considerations (unlikely, in our view), proving inducement must fail as a matter of law.

15